Opioid analgesics that are prescribed for pain management pose a significant health risk in terms of abuse potential and dose-dependent side effects. Emergency room visits and fatal poisonings caused by nonmedical use of these medications have more than double and tripled, respectively, within the last decade. Despite these alarming trends, opiate prescriptions continue to rise because of the prevalence and severity of chronic pain. One way to reduce the risks associated with opiates is to develop therapies that reduce the opiate dose necessary to achieve analgesia. A focal, non-invasive form of brain stimulation called repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential adjunctive therapy for pain management. Studies have shown that rTMS can reduce experimentally induced pain and chronic pain. In one study, a single session of postoperative left dorsolateral prefrontal cortex (DLPFC) rTMS reduced morphine self- administration by 40%. Before DLPFC rTMS can be evaluated as an adjunctive therapy for pain, studies need to reveal how it alters neuropharmacology and brain activity. There are many lines of indirect evidence that DLPFC mediates top-down analgesia via gain modulation of the supraspinal opioidergic circuit (SOC), including the periaqueductal gray (PAG) and rostroventromedial medulla (RVM). The purpose of this study is to examine whether DLPFC rTMS induces analgesia by activating the SOC. Hypothesis: Left DLPFC rTMS will induce a naloxone-reversible increase in pain tolerance that correlates with a naloxone-reversible increase in PAG-RVM BOLD signal. Specific Aims: (1) Characterize the time course and magnitude of DLPFC rTMS- induced analgesia. (2) Determine if left DLPFC rTMS-induced analgesia is sensitive to mu opioid blockade. (3) Identify the brain circuitry that underlies left DLFPC rTMS-induced analgesia and examine effective connectivity in that circuit. Methods: Aim 1 and 2 will be accomplished with a double sham-controlled, double- blind, crossover study. On the first experimental visit, participants will randomly receive intravenous saline or naloxone immediately prior to real or sham left DLPFC rTMS. One week later, participants will receive the same TMS treatment but the opposite IV infusion. A thermode will be used to assess pain perception via quantitative sensory testing on untreated skin and block testing on capsaicin-treated skin before and 0, 20 and 40 minutes after TMS treatment. Aim 3 will be accomplished using a similar study design inside of a 3T MRI scanner. Interleaved TMS-fMRI will be used to measure blood oxygen level-dependent (BOLD) signal changes induced by DLPFC rTMS. Dynamic causal modeling (DCM) analysis will be used to examine effective connectivity between DLPFC and PAG-RVM. Relevance to NINDS: Morbidity and mortality data associated with narcotic analgesics demonstrate an urgent need to discover adjunctive therapies for chronic and postoperative pain. This study uses rTMS as an interventional tool to study pain circuitry while simultaneously evaluating its potential as an adjunctive therapy for pain. PUBLIC HEALTH RELEVANCE: Despite an alarming rise in opiate abuse, prescriptions for narcotic analgesics continue to rise because of the prevalence and severity of chronic pain. Transcranial magnetic stimulation (TMS) is a non-invasive form of brain stimulation that has been shown to reduce pain in the laboratory and the clinic. The purpose of this study is to determine the mechanism by which TMS relieves pain so that it can be used to reduce the role of opiates in chronic and postoperative pain management.